N-cycloalkylmethyl decahydroisoquinolines

ABSTRACT

Cis-1-cyclopropylmethyl-3a-(substituted-phenyl) decahydroisoquinoline, useful as analgetic agonist and analgetic antagonist.

BACKGROUND OF THE INVENTION

It has long been known that slight chemical modifications of themorphine molecule lead to analgesic agonists of widely differing potencyand addictive properties. For example, codeine, the methyl ether ofmorphine, is a relatively mild analgesic agonist having slightdependance (addiction) liability. On the other hand, heroin, thediacetyl derivative of morphine, is a powerful agonist with extremelyhigh addiction potential. In addition, as long as 1915, Pohl found thatwhen the N-methyl group of codeine was replace with an allyl group, theresulting compound, N-allylnorcodeine, was an opiate antagonist. In1940, N-allylnormorphine or nalorphine was synthesized and was shown tohave a highly specific ability to reverse the depressant effects ofmorphine. Other simple chemical modifications of the morphine moleculehave yielded many interesting drugs. Thus, one fruitful research area inthe search for improved analgesics of high potency and/or lowerdependance (addiction) liability has been the chemical modification ofthe morphine molecule.

In addition to modifying the morphine ring structure by chemical means,chemists have developed a second related field of research--thepreparation of certain morphine partstructures--with the same end inmind as above; i.e., the synthesis of improved analgesic agonists and/oranalgesic antagonists of improved properties. For example, meperidine, awidely used analgesic, can be written as a morphine part-structure. Manyother morphine part-structures have been prepared, some of which haveimproved analgesic agonist properties and others, particularly thosewith an allyl group attached to a ring nitrogen, have opiate antagonistproperties. It had been hoped that morphine part-structure researchwould produce a compound having both opiate agonist and antagonistproperties since the opiate antagonist property would assure a user thatthe compound would have a greatly reduced dependance liability. Tworecently marketed analgesics, pentazocine and phenazocine, have beenfound to be both antagonists and agonists although they still retain acertain degree of opiate dependance liability.

One potential morphine part-structure can be written as adecahydroisoquinoline with an hydroxyphenyl group substituted on a ringjunction carbon atom para to the isoquinoline nitrogen. An attempt toprepare such a compound was described by Boekelheide in a paperappearing in J. Am. Chem. Soc., 69 790 (1947). This paper set forth thepreparation of what, according to the numbering system then in vogue,were 10-phenyldecahydroisoquinolines. It was the author's conclusion,however, that the compound (IX) had a cis configuration and (footnote 5)showed low analgesic activity. The synthesis itself is cumbersome andnot free from ambiguity. Sugimoto et. al., J. Pharm. Soc. Japan, 75 177(1955), C.A. 1956 1814b described the synthesis of 8 or 10-alkylateddecahydroquinolines. The reference also shows the morphinepart-structure, 10-)m-hydroxyphenyl)-3-methylisoquinoline [presentlynamed as1-methyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline]but without furnishing a synthesis for it. These authors do not, infact, describe the preparation of any decahydroisoquinoline, butdescribe only the preparation of the decahydroquinoline analogs.

Belgian Pat. No. 802,577 issued Jan. 19, 1974, discloses a generalmethod of preparing N-substituted 3a-phenyl, decahydroisoquinolines andspecifically discloses 3a-phenyl-3a-(m-methoxy phenyl) and3a-(m-hydroxyphenyl)-1-methyldecahydroisoquinolines,3a-(m-methyoxyphenyl) and3a-(m-hydroxyphenyl)-1-phenethyldecahydroisoquinolines, and1-cyclohexylmethyl-3a-phenyldecahydroisoquinoline.

SUMMARY OF THE INVENTION

This invention provides decahydroisoquinolines of Structure I below:##STR1## wherein R is cyclopropylmethyl or cyclobutylmethyl;

R' is O-alk, OH, or ##STR2## and alk is (C₁ -C₃) alkyl.

A preferred group of compounds of this invention are those in which R'is O-alk or OH and a particularly preferred group are those in which R'is OH only.

Also included within the scope of this invention arepharmaceutically-acceptable acid addition salts of the above basesformed with non-toxic acids. The term (C₁ -C₃) alk, for which alk is thesymbol, includes methyl, ethyl, isopropyl and n-propyl; thus, the termO-alk includes methoxy, ethoxy and the like. Similarly, ##STR3##includes acetoxy, propionoxy and butyroxy.

The pharmaceutically acceptable salts of the amine bases represented bythe above formula are formed with non-toxic acids, as for example, saltsderived from inorganic acids such as: hydrochloric acid, nitric acid,phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid,nitrous acid, phosphorous acid and the like, as well as salts derivedfrom non-toxic organic acids including aliphatic mono and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic andalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids,etc. Such pharmaceutically-acceptable salts thus include sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monhydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate,chloride, bromide, iodide, fluoride, acetate, propionate, decanoate,caprylate, acrylate, formate, isobutyrate, caprate, heptanoate,propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate,maleate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, phthalate, terephthalate, benzenesulfonates,toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,β-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate andthe like salts.

The bridgehead substituents, the meta-substituted phenyl at 3a and thehydrogen at 7a, can have either a cis or trans relationship to oneanother; i.e., the two substituents can be on the same "side" of thedecahydroisoquinoline ring system (cis) or on the opposite "side"(trans). In addition, both the 3a and 7a carbon atoms are asymmetric,thus giving rise in each compound to 4 optical isomers, occuring as tworacemates designated as the cis-dl and the trans-dl-pair Structure I isthus intended to comprehend both the optical isomers, the cis-dl andtrans-dl racemates, and their individual enantiomorphs since, as far asis known, all of the individual isomers and isomer mixtures are usefulas analgesic agonists or as analgesic antagonists; albeit largequantitative differences in analgesic agonist or antagonistic potencymay exist between individual isomers or racemates. We prefer, however,those compounds according to structure I above which are in the transconfiguration; i.e., the trans-dl racemic pair and the individual transisomers such as the trans-l compound.

The compounds of this invention are prepared according to the followingprocedure using the synthesis of compounds in which R' is methoxyl forpurely exemplarly purposes:

2-(2-Cyanoethyl)-2-(m-methoxyphenyl) cyclohexanone, prepared by themethod of Boekelheide, J. Am. Chem. Soc., 69, 790 (1947), is hydrolysedto 2-(2-carboxyethyl)-2-(m-methoxyphenyl) cyclohexanone. The free acidthus formed is reacted with ethyl chloroformate in the presence oftriethylamine to yield are acid anhydride which is in turn reacted withsodium azide. The product of this reaction, an acyl azide, is decomposedunder conditions which promote the Curtius rearrangement to yield anisocyanate which, upon refluxing with aqueous acid, yields an amine ofStructure III. This reaction sequence is illustrated below: ##STR4##

In carrying out the chemical transformations delineated in ReactionSequence 1, we prefer to hydrolyze the nitrile function of2-(β-cyanoethyl)-2-(m-methoxyphenyl)cyclohexanone using a mineral acidin a strongly acidic medium; for example, 12N aqueous hydrochloric acidin 60-70 percent aqueous acetic acid. Other mineral acids such assulfuric and phosphoric may also be used, as can a purely aqueousreaction medium, without affecting the yield or purity of the product inany way. Alkaline hydrolysis may also be used, but it is necessary touse somewhat more stringent reaction conditions in order to carry thehydrolysis past the intermediate amide stage to the salt of the freeacid. Higher boiling inert solvents such as diethyleneglycol can beused. The second step of the reaction sequence, the formation of an acidchloride or anhydride from the carboxylic acid of the previous step, canbe accomplished by use of any of the milder chlorinating agents, forexample, oxalyl chloride, thionyl chloride and the like to form an acidchloride or ethyl chloroformate to form an acid anhydride. We prefer touse ethyl chloroformate. An acid acceptor such as triethylamine can alsobe used to advantage in forming the desired acid chloride or anhydride,using an inert solvent. The reaction of the thus formed acid chloridewith sodium azide to form the acid azide is carried out under standardconditions. It should be recognized, however, that an alternateprocedure for preparing the azide exists; i.e., the formation of thehydrazide by reaction of anhydrous hydrazine with the acid chloridefollowed by azide formation with nitrous acid. Rearrangement of theazide under Curtius rearrangement conditions, consisting simply inheating the azide, however synthesized, at the reflux temperature ofbenzene or toluene for from 1 to about 24 hours, yields the expectedisocyanate. Acidification of the isocyanate product yields directly a3H-indole (III). The acidification is carried out by heating theisocyanate with a concentrated mineral acid as for example hydrochloricor sulfuric acid for from 12-24 hours. The product, as the free base, isisolated by basifying the acid reaction medium with, for example, sodiumhydroxide, sodium carbonate or the like.

Structure III above is named 3a-(m-methoxyphenyl)-3H-indole or3a-(m-methoxyphenyl)-3H-benzo[b]pyrrole and was prepared by Langlois etal. Tetrahdron, 27, 6541 (1971) using a different method of synthesis.Reaction Sequence 2 below outlines the production of the compounds ofthis invention represented by Structure I, from the intermediates ofReaction Sequence 1. The 3H-indole (III) end product of ReactionSequence 1 is methylated quantitatively to yield an iminium salt (IIIa)which compound is next reacted, also quantitatively, with diazomethaneto yield an aziridinium salt (IV). The aziridinium salt rearranges toproduce a mixture of double-bond isomers (Va and Vb). Reduction of theenamine isomer (Va) with sodium borohydride in acetic acid yields adecahydroisoquinoline-VI or VIa-(I above in which R' is methoxy).

The trans-dl-racemate (VI), is the predominant racemate isolated fromthis reaction with only minor quantities of the cis-dl-racemate (VIa)being found. Platinum hydrogenation also yields predominantly thetrans-dl-racemate. On the other hand, hydrogenation of the enamine (Va)with 5 percent palladium-on-carbon yields a mixture of the cis-dl- andtrans-dl 1 racemates (40-60), which racemates are readily separated fromeach other by precipitating the trans-dl racemate as a picrate salt. Thecis-dl racemate does not form an insoluble picrate. The above series ofreactions is illustrated below in Reaction Sequence 2: ##STR5##

In carrying out the procedures outlined in Reaction Sequence 2 above,alkylation of the 3H-indole (III) to yield the quaternary methylderivative (IIIa) is carried out preferably by treating the indole withtrimethyloxonium tetrafluoroborate. Other alkylating agents can,however, be used as for example dimethyl sulfate, methyl iodide and thelike. The product of this methylation reaction, an iodide or sulfatesalt, is then metathesized to the fluoroborate salt by reaction withfluoroboric acid. Transformation of this quaternary salt to anaziridinium salt (IV) named systematically as a salt of1-azonia-1-methyl-4-phenyl (or meta-substituted phenyl tricyclo[4,2,1,0¹⁻⁹ ] decane), is accomplished by reacting the iminium salt withdiazomethane. The diazomethane can be generated in situ or added as asolution in accordance with procedures long established in the art. Theaziridinium salt is rearranged to yield a mixture of double-bond isomers(Va and Vb) (85-15) by heating, preferably for about 1 hour at about200° C. although longer reaction times at somewhat lower temperatureswill give essentially the same yields. The direct product of therearrangement is an amine salt which must be treated with a base such assodium hydroxide or sodium carbonate in order to provide the thusproduced N-methyl octahydroisoquinolines (Va and Vb) as free bases. Thereduction of the (Va and Vb) to the corresponding decahydroisoquinolines(VI and VIa) has been discussed above.

Compounds according to structure VI or VIa containing ameta-hydroxyphenyl substituent at C-3a are prepared from thecorresponding methoxy compound by dealkylation using, for example,hydrobromic acid in acetic acid.

The preparation of compounds according to Formula I can be accomplishedby several procedures. As a starting point, the N-methyl derivative (VIabove) can be reacted with phenylchloroformate to yield a carbamate (Iwherein R is ##STR6## Hydrolysis of this carbamate provides thesecondary amine (I wherein R is H). Alkylation of the secondary amine bystandard procedures using a suitable cycloalkyl halide readily yieldsthe compounds of the invention according to I above wherein R is asdefined.

Alternatively, an amide can be formed with the secondary amine function(I wherein R is H) with an acylating agent ##STR7## and the resultingamide reduced to a tertiary amine function with LiAlH₄ or other similarreducing agent, to yield compounds according to I.

Compounds according to I above in which R' is O-alk, alk being otherthen methyl, can be prepared either by employing as a starting materiala 2-(2-cyanoethyl)-2-(m-alkoxyphenyl) cyclohexanone in which the alkoxygroup is ethoxy or propoxy, or can be derived from the m-hydroxyphenylderivative by any standard phenolic ether synthesis.

Compounds according to I above in which R' is ##STR8## are prepared bystandard acylation procedures from the corresponding compound in whichR' is OH, such acylation procedures involving, for example, the reactionof an anhydride ##STR9## a mixed anhydride, ##STR10## or an acidchloride ##STR11## with the phenol or preferably, an alkali metal saltthereof.

This invention is further illustrated by the following specificexamples.

EXAMPLE 1

A mixture was prepared containing 368 g. of2-(β-cyanoethyl)-2-(m-methoxyphenyl)cyclohexanone, 2000 ml. of glacialacetic acid 850 ml. of 12 N aqueous hydrochloric acid and 850 ml. ofwater. The mixture was refluxed for about 19 hours and then cooled toroom temperature. Sufficient ice and water were added to make a volumeof about 11 liters. The resulting mixture was stirred for about 30minutes at which point a precipitate comprising2-(β-carboxyethyl)-2-(m-methoxyphenyl) cyclohexanone formed. Thesupernate was removed by centrifugation, and the precipitate collected.The precipitate was thoroughly washed with water and then dried to yieldabout 280 g. of 2-(β-carboxyethyl)-2-(m-methoxyphenyl)cyclohexanonemelting at about 143-4° C. after recrystallization from water.

About 255 g. of 2-(β-carboxyethyl)-2-(m-methoxyphenyl)-cyclohexanonewere mixed with 125 g. of triethylamine and about 20 g. of sodiumsulfate. A solution of 99 g. of ethyl chloroformate in 3250 ml. ofanhydrous ether was added in dropwise fashion, thus converting thecarboxyethyl group to an acid anhydride. The reaction mixture wasstirred for about 1 hour at about 0° C. at which point 89 g. of sodiumazide in 350 ml. of water were added in dropwise fashion. After theaddition had been completed, the reaction mixture was stirred for anadditional two hours at 0° C. The organic layer was separated.2-(β-Azidoformylethyl)-2-(m-methoxyphenyl)cyclohexanone formed in theabove reaction was isolated as an oil by evaporation of the ether invacuo. The residual oil was dissolved in 3.5 1. of benzene, and thesolution heated at refluxing temperature for about 1.5 hours. Thebenzene was removed by evaporation in vacuo. By this procedure theazidoformyl group was rearranged under Curtius conditions to yield thecorresponding isocyanate. The benzene was removed by evaporation invacuo. The residual isocyanate was next hydrolyzed to the cyclic imineby heating overnight in a mixture containing 1200 ml. of water, 1200 ml.of glacial acetic acid and 1200 ml. of 12N aqueous hydrochloric acid.The hydrolysis mixture was cooled and then made strongly basic with 50percent aqueous sodium hydroxide.3a-(m-Methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindole thus procuced wasextracted into ether, and the ether layer separated, washed with waterand dried. Evaporation of the ether layer to dryness yielded 153.2 g. of3a-(m-methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindole, distilling atabout 140° C. at 0.07 mm/g. (For comparison, see Langlois et. al.,Tetrahedron, 27, 5641 (1971) compound 10 and page 5647, table 4,compound 42).

About 341 g. of 3a-(m-methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindolewere dissolved in 600 ml. of methyl ethyl ketone. 184 g. of dimethylsulfate were added to this solution in dropwise fashion. The reactionmixture was heated at refluxing temperature for 1 hour. 1100 ml. ofwater were then added over a one-half hour period and the reactionmixture refluxed for another 3 hours. The reaction mixture was madestrongly basic with 50 percent aqueous sodium hydroxide with externalcooling provided. 1-Methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6-heptahydroindole formed in the above reaction, beinginsoluble in the alkaline layer, separated and was extracted into ether.The ether extract was separated, washed with water and dried.Evaporation of the ether in vacuo left a residual oil comprising1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6heptahydroindole boiling atabout 144° C. at 0.4 mm/Hg; yield = 325.4 g.

325.4 g. of 1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6-heptahydroindole were dissolved in 2500 ml. of ether. A 50 percentmixture of 50 percent fluorboric acid and anhydrous ethanol was added indropwise fashion with stirring until the solution was acid to congo red.The ether layer was separated by syphoning. The aqueous layer whichcontained1-methyl-3a-(m-methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindoliniumfluoborate formed in the above reaction was allowed to stand while thefluoborate salt slowly crystallized. The salt was collected byfiltration, and the filter cake washed with ether. The filter cake wasthen triturated with an anhydrous ethanol-ether solvent mixture. Thesolvent was separated by filtration, and the filter cake was dried.Yield of the fluoroborate salt was about 392 g.

A solution of 55 g. of 1-methyl-3a-(m-methoxyphenyl)-2,3,3a,4,5,6,7-heptahydroindolinium fluoborate in 500 ml. of methylenechloride was cooled to about 0° C. A solution of diazomethane preparedfrom 103 g. of N-methyl-N-nitroso-p-toluenesulfonamide in ether wasadded over a 5-hour period. The reaction mixture was allowed to warm toroom temperature and was stirred overnight. The supernate was separatedfrom the precipitated oil comprising the fluoboroate salt of thecorresponding aziridinium compound,1-azonia-1-methyl-4-(m-methoxyphenyl)tricyclo[4,2,1,0^(2-8a) ] decane.The oily residue was triturated with three 1000 ml. portions of ether,and the ether washes were discarded. The residual oil was transferred toa 500 ml. round-bottom flask and heated at atmospheric pressure forabout 1 hour at 200° C., thus forming1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7-octahydroisoquinoline,which compound was dissolved in anhydrous ethanol, and the ethanolsolution treated with an excess of 50 percent aqueous sodium hydroxideand water. The octahydroisoquinoline, being insoluble in the alkalinesolution, separated and was extraced into ether. The ether extract wasseparated and dried, and the ether removed therefrom by evaporation invacuo.1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7-octahydroisoquinolinethus prepared distilled at about 168° C. at 0.5 mm/hg.

A mixture was prepared containing about 163 g. of1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7-octahydroisoquinoline, 90g. of sodium borohydride and 4500 ml. of tetrahydrofuran was cooled toabout 5° C. 1630 ml. of acetic acid were added in dropwise fashion whilemaintaining the temperature below about 10° C. The mixture was stirredfor one-half hour at about 5° C. and then gradually warmed to refluxingtemperature with mild heating. The mixture was refluxed for 1 hour, andwas then made strongly basic with about 3 liters of 25 percent aqueoussodium hydroxide. The tetrahydrofuran layer was decanted, and theaqueous layer washed with three 2-liter portions of ether. The ether andtetrahydrofuran layers were combined and evaporated to dryness in vacuo.The resulting residue, comprising1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineformed in the above reaction was dissolved in about 3.5 1 of ether, andthe ethereal layer washed with three 2 1. portions of water. The etherlayer was dried, and the ether removed therefrom by evaporation todryness in vacuo. The yield of the decahydroisoquinoline was 162.3 g.

The compound was purified via the picrate salt which was converted backto the free base by refluxing the salt with saturated lithium hydroxideat the ratio 30 g. of picrate to 1000 ml. of saturated aqueous lithiumhydroxide solution. Extraction of the free base into benzene followed bydistillation of the base yielded 1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline boiling in the range 145-79° C. at0.1 mm/Hg. The corresponding picrate salt melted at about 161-2° C.after recrystallization from aqueous ethanol. Overall yield through thesodium borohydride reduction procedure was about 90 percent.

Alternatively,1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7-octahydroisoquinoline wasreduced over platinum oxide with hydrogen to yield the correspondingdecahydroisoquinoline. 66.7 g. of the octahydro compound were dissolvedin 650 ml. of absolute ethanol. 5 g. of platinum oxide catalyst wereadded, and the hydrogenation mixture subjected to 60 psi of hydrogen.The yield of1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolinesynthesized by this procedure was about 96 percent. The compound wasagain isolated as the picrate salt.

The 1-methyl group was cleaved from the above decahydroisoquinoline bydissolving 8 g. of1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7.7a,8-decahydroisoquinolinein 64 ml. of methylene chloride and adding thereto a solution of 5.6 g.of phenyl chloroformate in 16 ml. of methylenechloride. The resultingmixture was refluxed for about 2 hours, and allowed to stand overnight.The solvents were then evaporated in vacuo. 100 ml. of 5 percent aqueoussodium hydroxide were added, and the resulting mixture stirred withwarming for about 15 minutes.1-Phenylcarboxy-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline formed in the above reaction, beinginsoluble in the basic layer, separated and was extracted into ether.The ether extract was separated and washed with water. The ether extractwas in turn extracted with 250 ml. of 10 percent aqueous hydrochloricacid followed by 250 ml. of water to remove any unreactedN-methyldecahydroisoquinoline. The ether layer was separated, dried, andthe ether removed by evaporation. The residue was refluxed for 66 hoursin 240 ml. of anhyrous ethanol and 50 ml. of 50 percent aqueouspotassium hydroxide. The volatile constituents were removed in vacuo andthe resulting concentrate extracted with ether. The ether extract wasseparated and dried. Evaporation of the ether left a residue comprising1-phenylcarboxy-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolinewhich was dissolved in 250 ml. of 10 percent aqueous hydrochloric acid.The acid layer was washed with ether, and the ether wash was discarded.The aqueous layer was made strongly basic with 50 percent sodiumhydroxide, and3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline thusformed was extracted into ether. The ether layer was separated, driedand the ether removed therefrom by evaporation. Distillation of theresulting residue yielded 5.5 g. of a3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline boilingat about 148° C. at 0.2 mm/Hg.

3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline wasconverted to the corresponding 3a-(m-hydroxyphenyl) derivative bytreatment with 50 percent HBr in 50 percent aqueous acetic acid. In thisprocedure, 5.2 g. of freshly distilled3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline weredissolved in 40 ml. of 50 percent aqueous hydrobromic acid and 40 ml. of50 percent aqueous a-(m-Hydroxyphenyl-acid. The resulting mixture wasrefluxed for 18 hours. The reaction mixture was cooled, diluted withabout 250 ml. of water and the pH thereof adjusted to about 10.4 with 50percent aqueous sodium hydroxide. The reaction mixture was treated witha 3:1 n-butanol-benzene solvent system.3a-(m-Hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline beinginsoluble in the alkaline layer passed into the organic layer. Theorganic layer was separated and dried, and the solvents removedtherefrom by evaporation in vacuo. 5 g. of3-(m-Hydroxyphenyl-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline wereobtained which melted at about 212°-214° C. with decomposition afterrecrystallization from dimethylformamide.

Analysis:Calc.: C, 76.67; H, 9.65; N, 6.39.

Found: C, 76.88; H, 9.35; N, 6.24.

EXAMPLE 2

Ten grams of3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline and11.7 ml. of triethylamine were dissolved in 170 ml. ofdimethylformamide. 11.4 g. of cyclopropylcarbonyl chloride were added tothis solution in dropwise fashion. The resulting mixture was heated inthe range 65-80° C. for about 2 hours, was cooled, and was the pouredinto about 1000 ml. of water.1-cyclopropylcarbonyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineformed in the above reaction was extracted therefrom with three 1000 ml.portions of ether. The ether extracts were combined and washed withthree 300 ml. portions of saturated aqueous sodium chloride followed byone 200 ml. water wash. The ether layer was separated, and dried, andthe ether removed therefrom by evaporation in vacuo. The dried residuewas dissolved in 100 ml. of THF (tetrahydrofuran) and this solutionadded dropwise to a solution of 6.5 g. of lithium aluminumhydride in 300ml. of THF. After the addition had been completed, the reaction mixturewas heated to reflux for about 4 hours. Next, about 75 ml. of ethylacetate were added to react with any excess lithium aluminumhydridepresent. Saturated ammonium tartrate was added to decompose inorganicsalts present and to cause them to coagulate. The THF solution wasseparated by decantation, and the residual salts washed with three 500ml. portions of THF. The THF washes were combined with the original THFlayer, and the solvent removed by evaporation to dryness in vacuo. Theresidual product comprising1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineformed in the above reaction was dissolved in 3 1. of ether. The ethersolution was washed with three 350 ml. portions of saturated sodiumchlorides solution aqueous followed by a 300 ml. water wash. The etherlayer was separated, dried and the ether removed by evaporation invacuo. Addition of ethyl acetate to the residual oil produced crystalsof1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolinewhich melted at about 164-6° C. after recrystallization from ethylacetate.

Analysis: Calc. for C₁₉ H₂₇ NO;

C, 79.97; H, 9.54; N, 4.91.

Found: C, 79.72; H, 9.63; N, 4.62.

The maleate salt was prepared from the free base: m.p. 146-8° C.

Analysis: Calc. for C₂₃ H₃₁ NO₅ :

C, 68.80; H, 7.78; N, 3.49.

Found: C, 68.52; H, 7.80; N, 3.68.

Other compounds of this invention prepared by the above procedureinclude: 1-cyclobutylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline maleate: m.p. 136-8° C.

Analysis: Calc. for C₂₄ H₃₃ NO₅ ; C, 69.37; H, 8.01; N, 3.33.

Found: C, 69.19; H, 7.79; N, 3.08.

1-Cyclopropylmethyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline maleate: m.p. 93-5° C.

Analysis: Calc. for C₂₄ N₃₃ NO₅ ;

C, 69.37; H, 8.01; N, 3.33.

Found: C, 69.17; H, 7.96; N, 3.29.

As previously stated, the compounds of this invention represented byformula I above contain two asymmetric centers, at 3a and 7a. Thus thecompounds can exist as four diastereoisomers occuring as two racemicpairs, commonly designated as the cis-dl and the trans-dl racemates.

The preparation of optically-active isomers of compounds according toStructure I, are illustrated below.

EXAMPLE 3

Thirty six and two-tenths grams of1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineand 23.4 g. of L(+)-mandelic acid were dissolved in 100 ml. ofisopropanol. The solvent was removed by evaporation and the residuerecrystallized from 1000 ml. of water. The resulting precipitateweighing 21.1 g. was separated by filtration and recrystallized from amixture of 28 percent acetone and 72 percent isopropyl ether. A sampleof the mandelate salt was treated with an excess of 1N sodium hydroxide.Trans-l(-)-1-methyl-3a-(m-methoxyphenyl-1,2,3,3a,4,5,6,7,7a,8-decahydrolisoquinolinebeing insoluble in the aqueous alkaline layer separated and wasextracted into ether. The ether was evaporated and the rotation of theresidual free base obtained by standard procedures. Therecrystallization of the L(+)-mandelate salt above from 28 percentacetone-72 percent isopropyl ether continued until the samples of theTrans-l(-)-1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydrolisoquinolineshowed a constant rotation after repeated recrystallization.Trans-l(-)-1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydrolisoquinolinethus prepared had a rotation of [α]₃₅₀ ²⁵.sup.° =- 48.1° .L(+)-mandelate salt;

Analysis:cal.: C, 72.96; H, 8.08; N, 3.40.

Found: C, 72.67; H, 8.21; N, 3.23.

The above procedure was repeated using D(-) mandelic acid in place ofL(+)-mandelic acid in the above procedure.Trans-d(-)-1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydrolisoquinolinethus obtained had the following rotation: [α]₃₅₀ ²⁵.sup.° = + 47.6° .

Following the procedure of Example 1 both the trans-l (+)-andtrans-d(-)-1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline isomers were N-demethylated andO-demethylated to yield respectively trans-l(+) andtrans-d(-)-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineisomers. N-acylation of the individual isomers with cyclopropylcarbonylchloride followed by reduction of the resulting amides with LiAlH.sub. 4by the procedure of Example 2 yieldedtrans-l(-)-1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydrolisoquinoline,maleate salt: m.p. 197.°-109° C.: [α]₃₅₀ ²⁵.sup.° = - 12.7; [α]_(d)²⁵.sup.° = - 3.8.

Analysis Calc.: C, 68.80; H, 7.78; N, 3.48;

Found: C, 68.70; H, 7.62; N, 3.31.

Trans-d(+)-1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydrolisoquinoline,maleate salt. m.p. 109.5°-110° C. [α]₃₅₀ ²⁵.sup.° = + 16.2; [α]_(d) ²⁵.sup.° = + 5.9.

Analysis:Calc.: C, 68.80; H, 7.78; N, 3.49;

Found: C, 68.56; H, 7.62; N, 3.26.

trans-l(-)-1-Cyclopropylmethyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineand its trans-d(+) isomer are prepared by the procedure of Example 2from the corresponding trans-l(-) andtrans-d(+)-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineswhich are in turn prepared by N-demethylation only of the trans-l(+) andtrans-d-(-)-1-methyl-3a-(m-methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineisomers provided by the procedure of Example 1.

Optically active isomers of the cis-dl-series; i.e.,cis-d-(+)-1-cyclobutyl-3a-(m-methoxyphenyl-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline,cis-l(-)-1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineand the like as well as the trans-dl-1 -cyclobutyl isomers are preparedin an entirely analogous fashion.

EXAMPLE 4 Preparation of Salts

Salts of the free bases of this invention, other than the mandelate ormaleate salts whose preparation is illustrated above, are prepared bydissolving the free base in ether and adding an equivalent of a suitablenon-toxic acid, also in ether. The salts thus formed, as for example thesulfate and phosphate salts, are insoluble in ether and can be isolatedby filtration. Alternatively, the amine base can be dissolved in ethanoland an equivalent of the acid added as an ethanolic solution. In thisinstance, since the salts thus formed are soluble in the reactionmixture, they are isolated by evaporation of the solvent in vacuo. Saltswhich can be formed by the above procedure include the hydrochloride,sulfate, hydrobromide, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, maleate, succinate, tartrate, citrate, benzoate, andp-toluene sulfonate salts of the N-cycloalkylmethyl3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolines ofthis invention and the corresponding m-alkoxy and m-acyloxy derivatives.

As previously stated, the compounds of this invention have bothopiate-agonist and opiate-antagonist properties. While the compounds arecapable of producing analgesia in mammals, the added characteristic ofbeing simultaneously opiate-antagonists greatly decreases the physicaldependence (addiction) liability of the particular drug. It might besaid that the opiate-antagonist activity of the compounds of thisinvention acts as a built-in safety device tending to mitigate anyphysical dependence-inducing (addictive) properties of the drug causedby its opiate-like analgesic action.

The compounds of this invention demonstrate their analgesic activity inthe mouse-writhing test and in the rat tail jerk assay, both standardpharmalcological assays for analgesic action. For example, the compoundsof this invention have demonstrated activity in inhibiting writhing inmice induced by the intraperitoneal injection of acetic acid and Table 1below sets forth the results of this assay. In the Table, column 1 givesthe name of the compund; column 2, the dosage in mg./kg. of mouseweight; column 3, the route of administration of the drug ("S.C." issubcutaneous and "or" is oral); and column 4, the percent inhibitionfound at the particular dose level. All readings were made at 0.5 hours.Median inhibiting doses (I.D.₅₀) are also included in the Table.

                                      Table 1                                     __________________________________________________________________________    Name of Compound     Dose  Route                                                                             % Inhibition                                   __________________________________________________________________________    Trans-dl-1-cyclobutylmethyl-3a-(m-                                                                 100   S.C.                                                                              100                                            hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-                                                              20    S.C.                                                                              100                                            decahydroisoquinoline maleate                                                                      2     S.C.                                                                              96                                               I.D..sub.50 S.C. ≃1.0 mg./kg.                                                      1     S.C.                                                                              46                                                                  100   or  100                                                                 20    or  36                                             Trans-dl-1-cyclopropylmethyl-3a-(m-                                                                100   S.C.                                                                              100                                            methoxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-                                                              20    S.C.                                                                              64                                             decahydroisoquinoline maleate                                                                      10    S.C.                                                                              20                                               I.D..sub.50 S.C. = 10-20 mg./kg.                                                                 100    or*                                                                              89                                               or = 20-50 mg./kg. 50    or  69                                                                  50     or*                                                                              79                                                                  100   or  87                                                                  20    or  13                                                                  20     or*                                                                              5                                              Trans-dl-1-cyclopropylmethyl-3a-(m-                                                                100   S.C.                                                                              100                                            hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-                                                              20    S.C.                                                                              99                                             decahydroisoquinoline maleate                                                                      10    S.C.                                                                              72                                               I.D..sub.50 S.C. = 2-5 mg./kg.                                                                   5     S.C.                                                                              66                                               or = 20-50 mg./kg. 2     S.C.                                                                              6                                                                   100   or  92                                                                  50    or  56                                                                  20    or  46                                             Trans-dl-1-cyclopropylmethyl-3a-(m-                                                                5      S.C.*                                                                            70                                             hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-                                                              2      S.C.*                                                                            43                                             decahydroisoquinoline (free base)                                               I.D..sub.50 S.C. = 2-5 mg./kg.                                              Trans-d(+)-1-cyclopropylmethyl-3a-(m-                                                              5      S.C.*                                                                            inact                                          hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-                                                              50     S.C.*                                                                            44                                             decahydroisoquinoline maleate                                                                      100    S.C.*                                                                            51                                             Trans-l(-)-1-cyclopropylmethyl-3a-(m-                                                              5      S.C.*                                                                            72                                             hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-                                                              2      S.C.*                                                                            47                                             decahydroisoquinoline maleate                                                 __________________________________________________________________________     *Reading made at 0.25 hours                                              

In all instances, the inhibitory action of the compounds in Table 1 inthe mouse writhing test was blocked by the administration of naloxoneexcept for compound 5, the trans-d(+) isomer, thus showing that thecompounds are opiate-like analgesics.

The compounds of this invention are also active in the rat tail jerkassay, another standard pharmacologic test for analgesic activity of theopiate-type. Such activity is manifested as an increase in the reactiontime of the animal in removing (jerking) its tail from a nearby heatstimulus (a resistance wire) after drug administration compared tocontrol time (no drug administered). Table 2 which follows gives theincreased reaction times over control times produced by the compounds ofthis invention when administered subcutaneously. Table 3 gives similarinformation for oral administration of the compounds. In Tables 2 and 3,column 1 gives the name of the compound; column 2, the dose; column 3,time of observation after administration of the drug; column 4, theincrease in reaction time above control in seconds; and column 5, thelevel of significance of the results ("p" value). A reaction time of 30seconds (approximately 24-25 sec. above control) is considered to bemaximal. All drugs were administered as aqueous solutions. More than onevalue for a given dose level indicates multiple determinations. Theresults are not averaged.

                                      Table 2                                     __________________________________________________________________________    Subcutaneous                                                                  __________________________________________________________________________                                     Increase in                                                             Time of                                                                             Reaction                                                                Observation                                                                         Time Over                                    Name of Compound   Dose    (Minutes)                                                                           Control                                                                             "p"                                    __________________________________________________________________________    Transd-dl-1-cyclobutylmethyl-3a-(m-                                                              0.25 mg./kg.                                                                          30    .71   .02                                    hydroxyphenyl)-1,2,3,3a,4,5,6,7,                                                                 0.5 mg./kg.                                                                           30    .21   .4                                     7a,8-decahydroisoquinoline maleate                                                               1 mg./kg.                                                                             10    .46   .05                                                               30    1.63  .001                                                              60    .17   .5                                                        2 mg./kg.                                                                             10    2.17  .001                                                              30    2.50  .001                                                              60    .96   .01                                                       10 mg./kg.                                                                            10    17.88 .001                                                              30    23.04 .001                                                              60    22.13 .001                                   Trans-dl-1-cyclopropylmethyl-3a-                                                                 80 mg./kg.                                                                            30    1.75  .02                                    (m-methoxyphenyl)-1,2,3,3a,4,5,                                                                          120   1.05  .1                                     6,7,7a,8-decahydroisoquinoline                                                maleate                                                                       Trans-dl-1-cyclopropylmethyl-3a-                                                                 0.5 mg./kg.                                                                           15    .75   .1                                     (m-hydroxyphenyl)-1,2,3,3a,4,5,6,                                                                1 mg./kg.                                                                             15    .50   .2                                     7,7a,8-decahydroisoquinoline                                                                     2 mg./kg.                                                                             15    2.21  .001                                   maleate            3 mg./kg.                                                                             15    2.04  .02                                                       5 mg./kg.                                                                             15    1.21  .01                                                               15    2.50  .01                                                               15    3.60  .01                                                       7 mg./kg.                                                                             15    4.25  .001                                                      10 mg./kg.                                                                            15    4.50  .001                                                              15    1.50  .01                                                               15    3.90  .01                                                       20 mg./kg.                                                                            15    5.17  .001                                                      20 mg./kg.                                                                            15    3.70  .001                                                      25 mg./kg.                                                                            15    4.40  .001                                                      30 mg./kg.                                                                            15    4.25* .01                                                       40 mg./kg.                                                                            15    3.90  .01                                                       50 mg./kg.                                                                            5     4.85**                                                                              .01                                                               10    4.95**                                                                              .01                                                               10    4.85* .001                                                              15    6.08* .001                                                              15    4.0   .01                                                               15    6.50**                                                                              .001                                                              15    5.98  .001                                                              30    5.10**                                                                              .01                                                               30    5.75  .001                                                              45    3.00  .001                                                              60    3.65  .01                                                               60    1.20  .05                                                               90    1.85  .01                                                               120   2.45  .01                                                               180   1.80  .01                                                       60 mg./kg.                                                                            15    4.40* .01                                                       100 mg./kg.                                                                           15    4.15  .01                                                       200 mg./kg.                                                                           15    5.65  .001                                   Trans-d(+)-1-cyclopropylmethyl-3a-                                                               10 mg./kg.                                                                            15    0                                            (m-hydroxyphenyl)-1,2,3,3a,4,5,6,                                                                50 mg./kg.                                                                            15    .25   .5                                     7,7a,8-decahydroisoquinoline                                                                             30    1.30  .01                                    maleate                    60    2.25  .05                                                               120   .10   .5                                                        100 mg./kg.                                                                           15    .50   .1                                                                30    1.55  .02                                                               60    3.50  .01                                                               120   1.15  .05                                    Trans-l(-)-1-cyclopropylmethyl-                                                                  0.1 mg./kg.                                                                           30    85    .2                                     3a-(m-hydroxyphenyl)-1,2,3,3a,4,                                                                 0.5 mg./kg.                                                                           30    1.30  .01                                    5,6,7,7a,8-decahydroisoquinoline                                                                 1 mg./kg.                                                                             30    0                                            maleate            2 mg./kg.                                                                             30    1.25  .05                                                               30    3.30  .001                                                              30    2.10  .01                                                       5 mg./kg.                                                                             10    2.75  .01                                                               15    3.45  .01                                                               30    3.55  .001                                                              30    2.95  .001                                                              30    6.65* .001                                                              30    6.95* .001                                                              60    1.0   .05                                                               120   0                                                                       180   0                                                               10 mg./kg.                                                                            10    7.30* .001                                                              15    5.80  .001                                                              15    6.70* .001                                                              30    3.25  .001                                                              30    7.90  .001                                                              60    3.0   .01                                                               90    2.55  .01                                                               120   4.0   .01                                                               180   1.50  .01                                                       50 mg./kg.                                                                            15    7.35  .001                                   __________________________________________________________________________     *20 sec. cut off                                                              **15 sec. cut off                                                        

                                      Table 3                                     __________________________________________________________________________    Oral                                                                          __________________________________________________________________________                                          Increase in                                                            Time of                                                                              Reaction                                                               Observation                                                                          Time Over                               Name of Compound        Dose   (Minutes)                                                                            Control                                                                              "p"                              __________________________________________________________________________    Trans-dl-1-cyclobutylmethyl-3a-(m-hydroxy-                                                            10 mg./kg.                                                                           10     .43    .3                               phenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroiso-                                                                  30     .63    .01                              quinoline maleate              60     .21    .4                                                       25 mg./kg.                                                                           30     1.71   .001                                                            60     1.04   .01                                                      50 mg./kg.                                                                           30     12.42  .01                              Trans-dl-1-cyclopropylmethyl-3a-(m-methoxy-                                                           20 mg./kg.                                                                           30     1.10   .01                              phenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroiso-                                                                  120    .20    .5                               quinoline maleate       80 mg./kg.                                                                           30     8.05   .2                                                              120    1.19   .05                              Trans-dl-1-cyclopropylmethyl-3a-(m-hydroxy-                                                           5 mg./kg.                                                                            15     0                                       phenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroiso-                                                           10 mg./kg.                                                                           15     .90    .2                               quinoline maleate       15 mg./kg.                                                                           15     .95    .05                                                      20 mg./kg.                                                                           15     1.45   .01                                                             15     .54    .2                                                              30     1.17   .01                                                             45     1.33   .01                                                      25 mg./kg.                                                                           15     2.10   .02                                                             30     .30    .3                                                       50 mg./kg.                                                                           10     2.83   .001                                                            10     2.73   .001                                                            10     2.88   .01                                                             15     4.25   .001                                                            15     4.92   .001                                                            15     5.08   .001                                                            30     1.50   .01                                                             30     3.83   .01                                                             30     3.17   .01                                                             45     2.25   .01                                                             45     5.63   .01                                                             45     2.25   .01                                                             45     1.79   .01                                                             60     2.42   .001                                                            90     1.38   .01                                                             120    1.17   .05                                                             180    - .13  .5                                                       100 mg./kg.                                                                          5      .55    .2                                                              10     2.45   .01                                                             15     4.85   .01                                                             15     7.46   .001                                                            15     5.45*  .001                                                            15     4.50   .001                                                            30     3.45   .001                                                            30     4.05   .01                                                             30     6.79   .001                                                            30     4.38   .001                                                            45     1.45   .05                                                             45     2.38   .001                                                            45     7.75   .001                                                            60     2.05   .01                                                      200 mg./kg.                                                                          15     7.25*  .001                                                            15     7.13*  .001                                                            30     2.75   .01                                                             30     1.42   .01                                                             45     5.79   .01                                                      300 mg./kg.                                                                          15     7.75   .001                             Trans-d(+)-1-cyclopropylmethyl-3a-(m-                                                                 100 mg./kg.                                                                          30     0      .3                               hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-deca-                                                                   60     0                                       hydroisoquinoline maleate      120    .40    .3                                                       150 mg./kg.                                                                          15     0                                                                      30     0                                                                      60     .35    .1                                                              120    .30    .5                                                              180    .30    .5                                                       200 mg./kg.   lethal                                  Trans-l(-)-1-cyclopropylmethyl-3a-(m-                                                                 5 mg./kg.                                                                            60     .20    .4                               hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-deca-                                                            10 mg./kg.                                                                           60     .65    .01                              hydroisoquinoline maleate                                                                             25 mg./kg.                                                                           60     1.30   .001                                                     50 mg./kg.                                                                           30     2.25   .01                                                             60     2.80   .001                                                            120    .80    .05                                                      100 mg./kg.                                                                          60     3.15   .001                                                     200 mg./kg.                                                                          30     4.90*  .001                                                            60     5.40   .001                                                            120    2.65   .001                             __________________________________________________________________________     *20 sec. cut off                                                         

The above effects could in each instance be blocked by theadministration of naloxone.

The ability of the compounds of this invention to antagonize the actionof morphine, an opiate, is shown by the following modification of theaforementioned rat tail jerk assay: The standard assay procedure is usedwith the exception that a 7 amps. current is used instead of a 6 amps.current in the hot wire to decrease the measurable agonist effects ofthe antagonist. The drugs under test are then administered to groups ofrats at different dose levels at different times prior to test, with a 5mg./kg. dose of morphine invariably being administered 10 minutes priorto test. Positive evidence of antagonism is a decreased reaction timeover that to be expected from the morphine. Suggestive evidence ofantagonism is the finding of a reaction time less than that to beexpected from the morphine dose added to the effect of the analgesicunder test as set forth in Tables 2 and 3. Among the compounds of thisinvention, those in which R in Structure I is cyclopropylmethyl are thepreferred antagonists, showing activity in the above test procedure. Forexample, trans-dl-1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolinefree base at a 50 mg./kg. oral dose administered 30 minutes prior totest reduces the analgesic response to 5 mg./kg. of morphineadministered 10 minutes prior to test. The corresponding maleate saltalso antagonizes the effects of morphine in the above test. In a seriesof determinations, it was ascertained that the minimum subcutaneous dosenecessary to reduce the analgesic effects of a 5 mg./kg. subcutaneousdose of morphine was in the range 2.5-5.0 mg./kg. and the minimum oraldose, 5-10 mg./kg. Subcutaneous dosages of 50 mg./kg. of theaforementioned maleate salt administered 30 and 60 minutes prior to theassay very effectively blocked the analgesic effect of 5 mg./kg. ofmorphine.

The optical isomers of the above compound are also opiate antagonist.For example,trans-d(+)-1-cyclopropylmethyl-3a-(m-hydroxypropyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolinemaleate shows morphine antagonistic effects in the above modified rattail jerk assay at 100 mg./kg. administered subcutaneously 60 minutesbefore test. The l(-) isomer shows antagonism at 1-2 mg./kg.administered subcutaneously, and also manifests antagonistic effects inblocking the morphine induced Straub tail in mice. In this assay, a 40mg./kg. dose of morphine was administered to mice 15 minutes prior toassay, and the test drug at various intervals before assay. Trans-dl-1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolinemaleate gave a 100 percent block of the Straubed tail effected by asubcutaneous injection of 40 mg./kg. of morphine when the test drug wasgiven at a dose of 50 mg./kg. subcutaneously 15 minutes prior to assay,and 80 percent when given 30 minutes prior to assay. The l(-) isomergave 100 percent blocking on the morphine-induced Straub tail at 50 and20 mg./kg. doses 15 and 30 minutes before assay.

Trans-dl-1-cyclopropylmethyl-3a-(m-methoxyphenyl)-1,2,3,3a,4.5,6,7,7a,8-decahydroisoquinolinealso was found to antagonize morphine in the rat tail jerk assay.

The compounds of this invention have subcutaneous toxicity (L.D.₅₀) ofabout 180-220 mg./kg. in mice and oral toxicity (L.D.₅₀) from about290-400 mg./kg. in mice. The l(-) isomer of trans-dl-1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinolineis less toxic than the dl mixture and the d(+) isomer has about the sametoxicity as the dl mixture.

The compounds of this invention can be employed to produce analgesia inmammals by administration by either the parenteral or oral route at a10-100 mg. dose level. For oral dosage, a suitable quantity of apharmceutically-acceptable salt of a base according to formula I, formedwith a non-toxic acid, is mixed with starch or other excipient, and themixture placed in telescoping gelatin capsules each containing ananalgesic dose. Similarly, the salt can be mixed with starch, a binder,and a lubricant, and the mixture compressed into tablets each containinga standard analgesic dose. The tablets may be scored if lower or divideddosages are to be used. With parenteral administration, theintramuscular or sub-cutaneous routes are preferred. For this purpose,aqueous solutions or suspensions are employed using apharmaceutically-acceptable salt of the amine base of formula 1. Ingeneral, modes of administration and pharmaceutical forms found usefulin the past for morphine, codeine, methadon, meperidine and otheropiate-like analgesics can be adopted by those skilled in the art forthe compounds of this invention. The dosages for the dl racemates andthe l isomers are in the range 10-100 mg. and preferably in the range25-50 mg.

We claim:
 1. A compound of the formula: ##STR12## wherein R iscyclopropylmethyl or cyclobutylmethyl;R' is O-alk, OH, or ##STR13## andalk is (C₁ -C₃) alkyl and pharmaceutically-acceptable acid-additionsalts thereof.
 2. A compound according to claim 1 in which R' is OH. 3.A compound according to claim 1 in which R' is O-alk and alk is (C₁ -C₃)alkyl.
 4. A compound according to claim 1 in which R iscyclopropylmethyl.
 5. A compound according to claim 1, said compoundbeingtrans-dl-1-cyclobutylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline.6. A compound according to claim 1, said compound beingtrans-dl-1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline.7. A compound according to claim 1, said compound beingtrans-l(-)-1-cyclopropylmethyl-3a-(m-hydroxyphenyl)-1,2,3,3a,4,5,6,7,7a,8-decahydroisoquinoline.8. A trans-dl racemate of a compound according to claim
 1. 9. A trans-dlracemate of a compound according to claim 1 in which R' is OH.